Bartter Syndrome, Diagnosis in Children

Bartter syndrome is a rare form of renal potassium wasting characterized by hypokalemia, normal blood pressure, vascular insensitivity to pressor agents, and elevated plasma concentrations of renin and aldosterone. In certain families, the disorder may be inherited as an autosomal recessive trait.

PATHOLOGY
Generalized hyperplasia of the juxtaglomerular apparatus, the site of renin production, is observed in most patients. The renal parenchyma is otherwise normal in most patients; a few have shown nonspecific glomerular disease, interstitial disease, or both.

PATHOGENESIS
The cause is unknown. Currently, the disorder is best explained as a primary defect in chloride reabsorption in the ascending limb of the loop of Henle. The resultant decrease in sodium chloride reabsorption in this portion of the loop reduces medullary hypertonicity, perhaps explaining the concentrating defect. The defect in chloride reabsorption presents extra sodium chloride to the distal tubule, where sodium is reabsorbed in exchange for potassium; the result is urinary potassium wasting. The induced hypokalemia stimulates the synthesis of prostaglandins (which may account for the vascular insensitivity to pressor agents and the defect in platelet aggregation); these, in turn, activate the renin-angiotensin-aldosterone system by increasing renin release and by stimulating aldosterone synthesis. The latter exacerbates renal potassium wasting.

CLINICAL MANIFESTATIONS
A severe form of Bartter syndrome (sometimes called hyperprostaglandin E syndrome) may afflict newborns. It is characterized by polyhydramnios, prematurity, dehydration secondary to marked urinary sodium, potassium and water loss, and growth failure; hypercalciuria and nephrocalcinosis are common. Young children typically present with growth failure, muscle weakness, constipation, and polyuria. Older children have muscle weakness or cramps and carpopedal spasms.

DIAGNOSIS
The diagnosis is suggested by the finding of hypokalemia; the serum potassium level is usually less than 2.5 mEq/L. Supportive findings include normal blood pressure; defective platelet aggregation; hypochloremia; metabolic alkalosis; elevated plasma levels of renin, aldosterone, and prostaglandin E2 ; and high urinary levels of potassium and chloride. Some patients may also have hypercalciuria, hyperuricemia, hypomagnesemia, and urinary sodium wasting. The diagnosis may be confirmed by the histologic demonstration of hyperplasia of the juxtaglomerular apparatus, but this abnormality is not found in all patients and is frequently absent in young children.

Bartter syndrome must be differentiated from licorice abuse, laxative or diuretic use, persistent vomiting or diarrhea, pyelonephritis, and diabetes insipidus. Several of these (laxative use, vomiting, diarrhea, diabetes insipidus) are associated with hypovolemia, which results in a low urinary chloride level, whereas Bartter syndrome is associated with an elevated level.

Bartter syndrome may be confused with Gitelman syndrome. Both disorders are associated with hypokalemia, renal potassium wasting, activation of the renin-angiotensin-aldosterone axis, and normal blood pressure. Gitelman syndrome commonly presents in older children and young adults with muscle weakness, carpopedal spasms, or tetany. Patients with Bartter syndrome have normal to decreased serum magnesium levels, normal urinary magnesium excretion, and normal to increased calcium excretion; patients with Gitelman syndrome have hypomagnesemia, increased urinary magnesium, and decreased calcium excretion. Gitelman syndrome results from a mutation of the gene for the thiazide-sensitive sodium-chloride co-transporter of the distal tubule located on chromosome 16.

TREATMENT
The goals of therapy are to supply adequate nutrition and to maintain the serum potassium level above 3.5 mEq/L. Therapy is initiated with oral potassium chloride supplementation, increasing the dose until the serum potassium level reaches 3.5 mEq/L or the dosage reaches 250 mEq/24 hr. Reasonably well tolerated potassium preparations include K-Lyte/Cl (Mead Johnson Company, Evansville, IN), flavored effervescent tablets containing 25 or 50 mEq of potassium chloride, and Micro-K 10 Extencaps (A.H. Robins Company, Richmond, VA). Sodium chloride supplementation may also be required in small children. If the serum potassium level remains below 3.5 mEq/L (mmol/L) after reaching a dose of 250 mEq/24 hr of potassium chloride, then triamterene, 5-10 mg/kg/24 hr in divided doses, should be added. If this fails to resolve the hypokalemia, then indomethacin, 3-5 mg/kg/24 hr divided into three doses, should be given. Patients receiving indomethacin should be monitored for signs of gastrointestinal irritation.

PROGNOSIS
The long-term prognosis of Bartter syndrome is uncertain. Many patients remain well, but some cases (especially those with glomerular or interstitial abnormalities) progress to renal insufficiency. Despite severe growth retardation in infancy, normal stature is ultimately obtained. The suggestion that mental retardation occurs in patients who have severe disease in the 1st yr of life remains to be confirmed.